Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Schmit, Stephanie L.; Edlund, Christopher K.; Schumacher, Fredrick; Gong, Jian; Harrison, Tabitha A.; Huyghe, Jeroen R.; Qu, Chenxu; Melas, Marilena; Berg, David J. Van Den; Wang, Hansong; Tring, Stephanie; Plummer, Sarah J.; Albanês, Demetrius; Alonso, M. Henar; Amos, Christopher I.; Anton, Kristen; Aragaki, Aaron K.; Arndt, Volker; Barry, Elizabeth L.; Berndt, Sonja I.; Bézieau, Stéphane; Bien, Stephanie A.; Bloomer, Amanda; Boehm, Juergen; Boutron-Ruault, Marie Christine; Brenner, Hermann; Brezina, Stefanie; Buchanan, Daniel D.; Butterbach, Katja; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Castelao, Jose E.; Chan, Andrew T.; Chang‐Claude, Jenny; Chanock, Stephen J.; Cheng, Iona; Cheng, Ya Wen; Chin, Lee Soo; Church, James M.; Church, Timothy R.; Coetzee, Gerhard A.; Cotterchio, Michelle; Correa, Marcia Cruz; Curtis, Keith R.; Duggan, David; Easton, Douglas F.; English, Dallas R.; Feskens, Edith J. M.; Fischer, Rocky; FitzGerald, Liesel M.; Fortini, Barbara K.; Fritsche, Lars G.; Fuchs, Charles S.; Gago‐Dominguez, Manuela; Gala, Manish; Gallinger, Steven; Gauderman, W. James; Giles, Graham G.; Giovannucci, Edward; Gogarten, Stephanie M.; González‐Villalpando, Clicerio; Gonzalez-Villalpando, Elena M.; Grady, William M.; Greenson, Joel K.; Gsur, Andrea; Gunter, Marc J.; Haiman, Christopher A.; Hampe, Jochen; Harlid, Sophia; Harju, John F.; Hayes, Richard B.; Hofer, Philipp; Hoffmeister, Michael; Hopper, John L.; Huang, Shu Chen; Huerta, José María; Hudson, Thomas J.; Hunter, David J.; Idos, Gregory; Iwasaki, Motoki; Jackson, Rebecca D.; Jacobs, Eric J.; Jee, Sun Ha; Jenkins, Mark A.; Jia, Wei Hua; Jiao, Shuo; Joshi, Amit D.; Kolonel, Laurence N.; Kono, Suminori; Kooperberg, Charles; Krogh, Vittorio; Küehn, Tilman; Küry, Sébastien; LaCroix, Andrea Z.; Laurie, Cecelia; Lejbkowicz, Flavio; Lemire, Mathieu; Lenz, Heinz Josef; Levine, David; Li, Christopher I.; Li, Li; Lieb, Wolfgang; Lin, Yi; Lindor, Noralane M.; Liu, Yun Ru; Loupakis, Fotios; Lu, Yingchang; Luh, Frank; Ma, Jing; Mancao, Christoph; Manion, Frank J.; Markowitz, Sanford D.; Martín, Vicente; Matsuda, Koichi; Matsuo, Keitaro; McDonnell, Kevin; McNeil, Caroline; Milne, Roger L.; Molina, A.; Mukherjee, Bhramar; Murphy, Neil; Newcomb, Polly A.; Offit, Kenneth; Omichessan, Hanane; Palli, Domenico; Cotoré, Jesús Paredes; Pérez-Mayoral, Julyann; Pharoah, Paul D.P.; Potter, John D.; Qu, Conghui; Raskin, Leon; Rennert, Gad; Riggs, Bridget M.; Schafmayer, Clemens; Schoen, Robert E.; Sellers, Thomas A.; Seminara, Daniela; Severi, Gianluca; Shi, Wei; Shibata, David; Shu, Xiao Ou; Siegel, Erin M.; Slattery, Martha L.; Southey, Melissa C.; Stadler, Zsofia K.; Stern, Mariana C.; Stintzing, Sebastian; Taverna, Darin; Thibodeau, Stephen N.; Thomas, Duncan C.; Trichopoulou, Antonia; Tsugane, Shoichiro; Ulrich, Cornelia M.; Duijnhoven, Fränzel J.B. van; Guelpan, Bethany van; Vijai, Joseph; Virtamo, Jarmo; Weinstein, Stephanie J.; White, Emily; Win, Aung Ko; Wolk, Alicja; Woods, Michael O.; Wu, Anna H.; Wu, Kana; Xiang, Yong Bing; Yen, Yun; Zanke, Brent W.; Zeng, Yi Xin; Zhang, Ben; Zubair, Niha; Kweon, Sun-Seog; Figueiredo, Jane C.; Wang, Zheng; Marchand, Loı̈c Le; Lindblom, Annika; Moreno, Vı́ctor; Peters, Ulrike; Casey, Graham; Hsu, Li; Conti, David V.; Gruber, Stephen B.

doi:10.1093/jnci/djy099

Cited by 144 publications

(163 citation statements)

References 36 publications

(33 reference statements)

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“…5 Polygenic risk scores derived from these studies have evaluated that some 5% of the study populations have over twofold increased risk of CRC. 32,33 In our study also, we observed an increased risk for individuals with increasing number of alleles causing a moderately increased CRC risk. However, polygenic risk scores do not take into account epistatic interactions, which may by far cause a more pronounced risk compared to single variants, as shown in our study.…”

Section: Discussionsupporting

confidence: 79%

“…So far, about 100 CRC susceptibility loci have been identified through genome‐wide association studies . Polygenic risk scores derived from these studies have evaluated that some 5% of the study populations have over twofold increased risk of CRC . In our study also, we observed an increased risk for individuals with increasing number of alleles causing a moderately increased CRC risk.…”

Section: Discussionsupporting

confidence: 65%

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Epistatic effect of TLR3 and cGAS‐STING‐IKKε‐TBK1‐IFN signaling variants on colorectal cancer risk

et al. 2019

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Objective The TLR3/cGAS‐STING‐IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Methods The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. Results Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11‐2.53, P‐value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07‐3.84, P‐value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03‐2.27, P‐value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5‐6 risk alleles compared to those with 0‐2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair‐wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. Conclusions Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 65%

Epistatic effect of TLR3 and cGAS‐STING‐IKKε‐TBK1‐IFN signaling variants on colorectal cancer risk

et al. 2019

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“…Traditional approaches of calculating the explained proportion of familial risk by common genetic variants have been widely employed in the GWAS literature . Manuscripts reporting on the newly identified susceptibility loci commonly estimate the incremental and total proportion of familial risk explained by the respective SNPs.…”

Section: Discussionmentioning

confidence: 99%

“…Manuscripts reporting on the newly identified susceptibility loci commonly estimate the incremental and total proportion of familial risk explained by the respective SNPs. For example, so far published estimates for the familial risk for CRC allegedly explained by common genetic variants ranged from ~6% for 10 SNPs, to ~8% for 20 SNPs under observation, to ~12% for 76 SNPs, to ~22% for 45 SNPs in a simulation study. Most studies took some LD measure into account, while others simply added up contributions of SNPs without LD‐pruning .…”

Section: Discussionmentioning

confidence: 99%

“…In the era of genome wide association studies (GWAS), many single nucleotide polymorphisms (SNPs) have been found to be associated with a higher risk for various types of cancers . With increasing sample size of the GWAS consortia, the power to detect common variants with small effects has rapidly increased, and discovery of several SNPs at once is now the rule rather than the exception …”

Section: Introductionmentioning

confidence: 99%

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Establishing a valid approach for estimating familial risk of cancer explained by common genetic variants

Weigl

Chang‐Claude

Hsu

et al. 2019

Intl Journal of Cancer

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We critically examined existing approaches for the estimation of the excess familial risk of cancer that can be attributed to identified common genetic risk variants and propose an alternative, more straightforward approach for calculating this proportion using well‐established epidemiological methodology. We applied the underlying equations of the traditional approaches and the new epidemiological approach for colorectal cancer (CRC) in a large population‐based case–control study in Germany with 4,447 cases and 3,480 controls, who were recruited from 2003 to 2016 and for whom interview, medical and genomic data were available. Having a family history of CRC (FH) was associated with a 1.77‐fold risk increase in our study population (95% CI 1.52–2.07). Traditional approaches yielded estimates of the FH‐associated risk explained by 97 common genetics variants from 9.6% to 23.1%, depending on various assumptions. Our alternative approach resulted in smaller and more consistent estimates of this proportion, ranging from 5.4% to 14.3%. Commonly employed methods may lead to strongly divergent and possibly exaggerated estimates of excess familial risk of cancer explained by associated known common genetic variants. Our results suggest that familial risk and risk associated with known common genetic variants might reflect two complementary major sources of risk.

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Single-Nucleotide Polymorphism–Based Genetic Risk Score and Patient Age at Prostate Cancer Diagnosis

Labbate

et al. 2019

JAMA Netw Open

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IMPORTANCE Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. OBJECTIVES To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. DESIGN, SETTING, AND PARTICIPANTS A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. INTERVENTIONS A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk-associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (<0.50), average (0.50-1.49), and high (Ն1.50). MAIN OUTCOMES AND MEASURES Prostate cancer diagnosis-free survival among men of different risk groups. RESULTS Among 3225 men (median age, 63 years [interquartile range, 58-67 years]) in the study, 683 (21%) were classified as low risk, 1937 (60%) as average risk, and 605 (19%) as high risk based on GRS alone. In comparison, 2789 (86%) were classified as low or average risk and 436 (14%) as high risk based on FH alone. Men in higher GRS risk groups had a PCa diagnosis-free survival rate that was worse than that of those in the lower GRS risk group (χ 2 = 53.3; P < .001 for trend) and in participants with a negative FH of PCa (χ 2 = 45.5; P < .001 for trend). Combining GRS and FH further stratified overall genetic risk, indicating that 957 men (30%) were at high genetic risk (either high GRS or positive FH), 1667 men (52%) were at average genetic risk (average GRS and negative FH), and 601 men (19%) were at low genetic risk (low GRS and negative FH). The median PCa diagnosisfree survival was 74 years (95% CI, 73-75 years) for men at high genetic risk, 77 years (95% CI, 75 to >80 years) for men at average genetic risk, and more than 80 years (95% CI, >80 to >80 years) for men at low genetic risk. In contrast, the median PCa diagnosis-free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH.

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Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Abstract: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Cited by 144 publications

References 36 publications

Epistatic effect of TLR3 and cGAS‐STING‐IKKε‐TBK1‐IFN signaling variants on colorectal cancer risk

Epistatic effect of TLR3 and cGAS‐STING‐IKKε‐TBK1‐IFN signaling variants on colorectal cancer risk

Establishing a valid approach for estimating familial risk of cancer explained by common genetic variants

Single-Nucleotide Polymorphism–Based Genetic Risk Score and Patient Age at Prostate Cancer Diagnosis

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